| Complex diseases are conditions that are influenced by the actions of multiple genes, their interactions with each other and with the environment. The prevalence of complex diseases is higher than 1% in general population, hence also called common diseases, such as schizophrenia, major depresive disorder, bipolar disorder, cardiovascular disease, et al. With the increase of social pressure and the speedup of social life, people are paying more and more attention to psychiatric disorders. The first and second parts of my thesis is about linkage disequilibrium study on YWHAE and CTLA-4 genes of schizophrenia, major depresive disorder, and bipolar disorder in Chinese Han population. YWHAE is a gene encoding 14-3-3epsilon, which is highly conserved across species, from bacteria to humans, and binds to phosphoserine/phosphothreonine motifs in a sequence-specific manner.YWHAE has been reported to be associated with schizophrenia in a study based on the Japanese population. Here, we conducted a genetic association analysis between common SNPs in the YWHAE gene and psychiatric diseases including schizophrenia, major depressive disorder and bipolar disorder in Han Chinese samples (1140 schizophrenia cases, 1140 major depressive disorder cases, 1140 bipolar disorder cases and 1140 normal controls). We studied 11 SNPs, 7 of which had previously been reported as significant, in YWHAE. No association was found with schizophrenia, major depressive disorder or bipolar disorder. Considering the size of our sample sets (power>90%), our results suggest that the YWHAE does not play a major role in schizophrenia, major depressive disorder or bipolar disorder in the Han Chinese population. Ikeda M et al. identified YWHAE, as a possible susceptibility gene for schizophrenia in the Japanese population. YWHAE encodes 14-3-3epsilon, which is an interacting partner of DISC1. DISC1 has been identified as a potential susceptibility gene for major psychiatric disorders including schizophrenia, depressive disorder and bipolar disorder. Several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major psychiatric illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. As an interacting partner of DISC1, 14-3-3epsilon may also play an important role in the development of these psychiatric disorders. In 2005, Yanagi et al.'s study showed that YWHAE is associated with suicide in the Japanese population, but to date, no other studies about the relationship of YWHAE and major depressive disorder or bipolar disorder have been reported. To investigate whether the YWHAE gene plays a significant role in psychiatric diseases, we focused on the YWHAE gene in schizophrenia, major depressive disorder and bipolar disorder in Han Chinese samples involving 1140 schizophrenia patients, 1140 major depressive disorder cases, 1140 bipolar disorder patients and 1140 normal controls. We genotyped 11 SNPs in YWHAE, including all the seven positive SNPs in Ikeda M et al.'s study (rs34041110, rs7224258, rs3752826, rs11655548, rs2131431, rs1873827 and rs28365859), and also selected additional four Tag SNPs (rs12452627, rs1532976, rs8064578, rs7225165) from the HapMap database to provide a good coverage of the gene. In schizophrenia group, only rs1873827, rs3752826, rs12452627 and rs7225165 are marginally associated with schizophrenia, but after 10,000 permutations, there was no association. In major depressive disorder group, only rs34041110, rs12452627 and rs7225165 show some marginal relationship with major depressive disorder, but no association after 10,000 permutations. In bipolar disorder group, rs1873827, rs1532976 and rs7225165 show some marginal association with bipolar disorder, but this was not remained after 10,000 permutations. In all we found that YWHAE has no association with these major mental disorders in the Han Chinese population, although several loci have marginal association with one or all of these disorders before permutations. It is a general problem that the association of one gene with complex diseases in one population cannot be replicated in another population. It may depend on the different LD blocks between different populations or on the different frequency of alleles between populations. Another reason that leads to the inconsistency may be the different endophenotypes that exist. In summary, this first case-control study based on samples in the Chinese population failed to prove the 11 SNPs of YWHAE with susceptibility to schizophrenia, major depressive disorder or bipolar disorder in general. Though we found no association, considering the current sample size and the effect size (OR=0.67) from the previous study, the power > 90% (we used the tool of GPower 3.1), our results can provide a reference for further studies of YWHAE gene in other populations. Further work with large sample size or from different populations and corresponding functional analysis is still required to fully elucidate the exact role of YWHAE in the pathogenesis of schizophrenia and other psychiatric disorders.Previous studies have reported that the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene, which is related to immunological function such as T-cell regulation, is associated with psychiatric disorders. It is involved in establishing and maintaining peripheral T-cell tolerance, which controls T-cell activation and reactivity. The CTLA-4 gene is located on the long arm of chromosome 2q33. It consists of 4 exons and encodes a costimulatory molecule that is expressed on the surface of activated T cells. Based on function and experimental data, it has been suggested as a candidate gene for conferring susceptibility to autoimmune disease. Moreover, several researchers have reported the association of common SNPs in CTLA-4 with schizophrenia or major depressive disorder. 3 SNPs (rs231775, rs3087243, rs5742909) have been analyzed in previous studies. Jun et al. reported significant association of rs231775 (A49G) in exon 1 with schizophrenia but not with major depressive disorder in the Korean population. However, Jones et al. found that in males, both the promoter region rs5742909 (-318C/T) and the 3'UTR SNP rs3087243 demonstrated nominally significant association with schizophrenia in Caucasian populations. In this study, we studied the relationship between CTLA-4 and three major psychiatric disorders, schizophrenia, major depressive disorder and bipolar disorder in the Chinese Han population. We recruited 1140 schizophrenia patients, 1140 major depressive disorder patients, 1140 bipolar disorder patients, and 1140 normal controls to examine the risk conferred by 6 tag SNPs (rs231777, rs231775, rs231779, rs3087243, rs5742909, rs16840252) in the CTLA-4 gene. For schizophrenia, rs231777 (Pallele = 0.0201), rs231779 (Pallele = 0.0003, Pgenotype = 0.0016) and rs16840252 (Pallele = 0.0081, Pgenotype = 0.0117) showed nominal significance in the tests and after 10,000 permutations, rs231779 remained significant (Pallele = 0.0010, Pgenotype = 0.0145). For major depressive disorder, only rs231779 (P allele= 0.0006, Pgenotype = 0.0026) showed nominal significance in the tests and after 10,000 permutations it remained significant (Pallele = 0.0010, Pgenotype = 0.0201). For bipolar disorder, rs231777 (Pallele=0.0199), rs231779 (Pallele = 0.0004, Pgenotype = 0.0018) showed nominal significance in the tests. After 10,000 permutations, only rs231779 remained significant (Pallele = 0.0008, Pgenotype = 0.0125). This result is very interesting, as it has been hypothesized that some genes will influence the risk for relatively specific domains of psychopathology, whereas others will have a more general influence on the risk. In conclusion, our case-control study provides the evidence that CTLA-4 may play a role in the susceptibility to major psychiatric disorders in Han chinese population. Although the significant associated SNP rs231779 in this study located in the intron, we can't exclude its possible role in the expression of CTLA-4. Our result is a clear demonstration that there is an overlap in the biological underpinnings of susceptibility to mental illness across the clinical spectrum of mood and psychotic disorders. At least some psychiatric patients with immune alterations may partially share the aetiology, development and pathogenic mechanism of the disease. However, furthermore studies for the functional role that CTLA-4 may play in the psychiatric disorders are needed, and it will give some new information which is useful for the diagnosis and therapy of these diseases. And all of this will be useful in influencing psychiatric research to move from reliance on a diagnostic and classification system that is based only on clinical description and towards a scheme that better reflects the underlying biology of the psychiatric entities encountered in our clinics. This will be of great benefit to patients. Our data, based on Han Chinese population in this study, have given some cues about this.Another part of our work is about the ENU (ethylnitrosourea) mutagenesis mouse model. ENU is a synthetic compound described as the most potent mutagen in mice. Large-scale ENU mutagenesis program has provided us with a large number of new mouse mutants applied for the analysis of gene function and further for good models of some human diseases. We screened circling phenotype mice by ENU mutagenesis, mapping the related gene in chromosome 4 and sequenced a novel mutant in exon13 of mouse CHD7 gene. This novel mutant resulted in functional change from arginine to premature stop codon. It has been reported that human CHD7 gene was linked to autosome dominant disease CHARGE syndrome. CHARGE syndrome follows an autosomal dominant mode of inheritance. Its incidence of 1:8500 was evaluated in a Canadian study and is suggested to range between 0.1and1.2/10,000 live births. Mutations in the chromodomain helicase DNA-binding protein 7 (CHD7) gene in 8q12.1 were identified as causative for CHARGE syndrome. The gene has 37 coding exons and encodes a 2997-amino acid protein that belongs to the family of chromodomain helicase DNA-binding (CHD) proteins. In humans at least nine CHD genes are known. Functional domains such as chromo (chromatin organization modifier), SNF2- related helicase/ATPase and BRK were identified in the CHD7 protein. The majority of CHD7 gene mutations is unique and occurs de novo. On the basis of the overlap in clinical features between CHD7 mutant mice and CHARGE, we believe that these mice will be a valuable tool in further analysis of the pathology underlying the abnormalities in CHARGE syndrome. |
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